One major advance in our understanding of prostate cancer pathogenesis is the recent seminal discovery that more than half of prostate cancers contain a fusion between TMPRSS2, a gene that is highly expressed in the prostate, and the ERG transcription factor. The role of TMPRSS2-ERG fusion in prostate cancer pathogenesis is poorly understood. A crucial limitation to our understanding is the lack of model systems. In this proposal, using three novel genetically-targeted mice, I will attempt to answer the following four questions: 1) where is TMPRSS2 expressed in the prostate and what is the fate of TMPRSS2-expressing cells? 2) what is the phenotype of mice expressing ERG under the TMPRSS2 promoter? 3) within the prostate, which cell types are sensitive to ERG-mediated transformation? and 4) what other genetic events cooperate with TMPRSS2-ERG fusion in carcinogenesis? First, I will generate a mouse expressing an inducible recombination enzyme (tamoxifen-inducible Cre) under the TMPRSS2 promoter, allowing detailed mapping of TMPRSS2 expression patterns and determination of the fate of TMPRSS2-expressing cells in the prostate. This mouse can also be used to activate oncogene/tumor suppressors in TMPRSS2-expressing cells when crossed with previously generated mice that have Cre inducible lesions. Second, I will target the ERG gene into the TMPRSS2 locus. This mouse will be assessed for tumor development, and the prostates will be studied in detail with histology and expression profiling. Third, I wilt target a Cre-inducible ERG into the ubiquitously expressed Rosa26 locus such that ERG will be specifically expressed when crossed with mice harboring tissue-specific Cre that is active in other prostate compartments. Fourth, to find genetic events that cooperate with TMPRSS2-ERG fusion, I will utilize both a candidate approach (crossing with previously generated mouse models harboring genetic lesions found in human prostate cancers) and an unbiased screen approach utilizing transposon mutagenesis that will specifically be activated in TMPRSS2 expressing cells. These studies will offer a comprehensive understanding of the role of TMPRSS2-ERG fusion in prostate cancer.